Synthesis method of camptothecin derivative

Abstract

The present invention relates to the technical field of camptothecin derivative preparation, particularly to a camptothecin derivative synthesis method, which uses 2-nitroacetophenone and isopropylamine as raw materials, and the camptothecin derivative is obtained through a Mannich reaction, a methylsulfonylation reaction, a nitro reduction reaction and a ring closing reaction. According to the synthetic method of the camptothecin derivative, the complex camptothecin derivative is split into two segments 1-(2-aminophenyl)-3-(N-isopropyl-N-methylsulfonylamino) propan-1-one and a compound V which are easy to prepare, and finally, a plurality of rings and chemical bonds are constructed simultaneously through one-step efficient ring closing reaction. The yield attenuation caused by progressive multiplication of the yield in the traditional linear synthesis is avoided, and the total yield is improved.

Description

Technical Field

[0001] This invention relates to the field of camptothecin derivative preparation technology, and in particular to a method for synthesizing camptothecin derivatives. Background Technology

[0002] Camptothecin derivatives possess topoisomerase I inhibitory activity and are the cellular active fragment in the ADC drug, luconsautuzumab for injection. Luconsautuzumab for injection is indicated for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received at least two prior systemic therapies (at least one of which was for advanced or metastatic stages). The synthesis of camptothecin derivatives mainly involves two methods: total synthesis and semi-synthesis. The total synthesis method, developed by Sang-sup Jew et al. in South Korea, uses o-nitrothecoacetone as a starting material and proceeds through five steps: Mannich reaction, benzyloxycarbonyl protection, sodium hydrosulfite reduction, cyclization reaction, and deprotection to obtain beloteccan. Beloteccan is then subjected to mesylation to yield compound VI, as shown in the reaction formula below. .

[0003] In the above total synthesis method, the overall yield is approximately 1.86%, which is too low, resulting in exceptionally high actual production costs and limited practical value. The semi-synthetic method, developed by Soon Kil Ahn et al. in South Korea, uses camptothecin as a starting material and proceeds through two steps: methylation and the Mannich reaction, to obtain beloteccan. Beloteccan then undergoes mesylation to yield compound VI, as shown in the reaction formula below. .

[0004] In the aforementioned semi-synthetic methods, the Mannich reaction produces numerous byproducts, resulting in low yields and difficulties in purification, thus limiting the application of this route. Therefore, a simpler, higher-yield, and lower-cost synthetic method for camptothecin derivatives remains needed. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing camptothecin derivatives, which is simple, has a high yield, and is low in cost.

[0006] To achieve the above objectives, the present invention provides a method for synthesizing camptothecin derivatives, comprising the following steps: S1. Add 2-nitroacetophenone, paraformaldehyde, isopropylamine, and hydrochloric acid to isopropanol, heat and stir to react, concentrate under reduced pressure after the reaction is complete, extract to remove impurities in the aqueous layer, adjust the pH of the aqueous layer, extract again, dry the organic phase, filter and concentrate under reduced pressure to obtain 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one. S2. The 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one and N,N-diisopropylethylamine obtained in S1 are added to dichloromethane, and a methanesulfonylating agent is added to react at room temperature to obtain 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one. S3. Add the 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one obtained in S2 to methanol and stir to carry out nitro reduction reaction to obtain 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one. S4. The 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one obtained in S3 and compound V were subjected to a cyclization reaction under acidic conditions to obtain camptothecin derivatives.

[0007] Preferably, in S1, the temperature of the heating and stirring reaction is 80-100℃, and the time is 1-24h.

[0008] Preferably, in S2, the methanesulfonating agent includes one or more of methanesulfonyl chloride and methanesulfonic anhydride.

[0009] Preferably, in S2, after the reaction is complete, dilute hydrochloric acid is added for separation, the organic phase is washed, dried and filtered, and the crude product is dissolved, crystallized, filtered and dried to obtain 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one.

[0010] Preferably, in S3, the nitro reduction reaction includes one of the following: catalytic hydrogenation, metal reduction, transfer hydrogenation, and sulfide reduction.

[0011] Preferably, in S3, hydrogen and a catalyst are added during the catalytic hydrogenation reaction, and the catalyst is one of palladium on carbon, platinum on carbon, and Raney nickel; One or more of iron powder, stannous chloride, and zinc powder are added during metal reduction reactions; Palladium on carbon and a hydrogen donor are added during the transfer hydrogenation reaction. The hydrogen donor is one of ammonium formate, cyclohexene, and hydrazine hydrate. One or more of sodium sulfide, sodium hydrosulfide, ammonium sulfide, sodium dithionite, and sodium thiosulfate are added during the sodium sulfide reduction reaction.

[0012] Preferably, in S3, the nitro reduction reaction temperature is 0-40℃, the reaction time is 5-48h, the reaction is filtered, hydrochloric acid is added to the filtrate and the solution is concentrated under reduced pressure, the crude product is dissolved and crystallized, filtered and dried to obtain 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one.

[0013] Preferably, in S4, the structural formula of compound V is as follows: .

[0014] Preferably, in S4, the acidic conditions are achieved by adding p-toluenesulfonic acid monohydrate and one of toluene and N-methylpyrrolidone, and the cyclization reaction is carried out at a temperature of 80-150°C for 5-24 hours.

[0015] Preferably, in S4, after the cyclization reaction is complete and the temperature is lowered to room temperature, the resulting reaction solution is added to water and stirred. After filtration, a crude product is obtained. The crude product is then added to methanol and stirred. After filtration and drying, a camptothecin derivative is obtained.

[0016] Therefore, the present invention employs the above-mentioned method for synthesizing a camptothecin derivative, and its beneficial effects are as follows: 1. The synthetic method provided by this invention uses inexpensive raw materials to split the complex camptothecin derivative into two easily prepared fragments, 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one (compound IV) and compound V. Finally, multiple rings and chemical bonds are constructed simultaneously through a one-step efficient ring-closing reaction, avoiding the yield decay caused by the stepwise accumulation of yields in traditional linear synthesis, and achieving an improvement in the overall yield. 2. The synthesis method provided by this invention has simple steps, mild conditions, and safe operation. It adopts a simple purification process, which is suitable for industrialization, avoids expensive consumables, and significantly reduces production costs.

[0017] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0018] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one in Example 1 of the present invention; Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one in Example 1 of this invention; Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one in Example 1 of the present invention; Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the camptothecin derivative in Example 1 of the present invention. Detailed Implementation

[0019] The present invention will be further described below with reference to the accompanying drawings and embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should be understood in their ordinary sense by those skilled in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0020] This invention provides a method for synthesizing camptothecin derivatives, as shown below: .

[0021] Includes the following steps: S1. 2-Nitroacetophenone (compound I), paraformaldehyde, isopropylamine, and hydrochloric acid were added to isopropanol and heated and stirred to react. After the reaction was completed, the mixture was concentrated under reduced pressure, and the aqueous layer was extracted to remove impurities. The pH of the aqueous layer was adjusted, and the mixture was extracted again. The organic phase was dried, filtered, and concentrated under reduced pressure to obtain 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one (compound II). In this step, 2-nitroacetophenone and isopropylamine undergo the Mannich reaction. Formaldehyde and isopropylamine condense under acid catalysis and dehydrate to generate an imine ion intermediate. 2-Nitroacetophenone is enolized under acidic conditions. The enol formed acts as a nucleophile to attack the carbon atom of the imine ion, introducing a side chain with isopropylamine onto the α-carbon of 2-nitroacetophenone to form compound II.

[0022] .

[0023] S2. The 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one and N,N-diisopropylethylamine obtained in S1 are added to dichloromethane, and a methanesulfonylating reagent is slowly added and reacted at room temperature to give 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one (compound III). In this step, N,N-diisopropylethylamine first neutralizes the amine salt and abstracts a proton from the amino group to generate a free secondary amine nucleophile. The secondary amine nucleophilically attacks the sulfur atom of the methanesulfonylating reagent, and an SN2 nucleophilic substitution reaction occurs. The chloride ion leaves, converting the secondary amine into methanesulfonamide. The acidity of the hydrogen atom on the nitrogen atom is enhanced, creating the necessary reactivity for the transformation of this group in the subsequent ring-closing reaction.

[0024] .

[0025] S3. The 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one obtained in S2 is added to methanol and stirred to carry out the nitro reduction reaction, yielding 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one (compound IV). In this step, the nitro group is gradually reduced, passing through intermediates such as nitroso and hydroxylamine, and finally generating an amino group. The nitro group on the aromatic ring is reduced to an amino group. This newly generated ortho-amino group is a strong nucleophilic center, which is the key to driving the next ring-closing reaction.

[0026] .

[0027] S4. The 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one obtained in S3 and compound V were subjected to a ring-closure reaction under acidic conditions to obtain the camptothecin derivative compound (compound VI). In this step, the aromatic amino group of compound IV and the aldehyde group of compound V under acid catalysis undergo dehydration condensation to form an imine intermediate. Under acid catalysis, the enolization product of the acetophenone moiety of compound IV acts as a nucleophile to attack the carbon atom of the imine in the molecule, forming a new C-C bond and constructing a C ring. The two key fragments, compound IV and compound V, prepared separately, are then combined through a condensation reaction to construct the complex A, B, C, and D tetracyclic skeleton of the camptothecin derivative in one step.

[0028] .

[0029] In some embodiments of the present invention, in S1, the heating and stirring reaction is carried out at a temperature of 80-100°C for 1-24 hours. The Mannich reaction is conducted under heating conditions to promote the formation of imine ions from formaldehyde and amines, as well as the enolization of ketones. Controlling the reaction temperature and time in this invention ensures efficient and complete reaction with controllable side reactions.

[0030] In some embodiments of the present invention, in S2, the methanesulfonating agent includes one or more of methanesulfonyl chloride and methanesulfonic anhydride. The methanesulfonating agent is an effective donor of the methanesulfonyl group and can undergo a nucleophilic substitution reaction with an amine to generate a stable methanesulfonamide bond.

[0031] In some embodiments of the present invention, in step S2, after the reaction is complete, dilute hydrochloric acid is added for separation, and the organic phase is washed, dried, and filtered. The crude product is dissolved, crystallized, filtered, and dried to obtain 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one. Excess alkali is removed by acid washing, and recrystallization is performed to purify the compound III by taking advantage of its good solubility in ethyl acetate but a sharp decrease in solubility in the nonpolar solvent petroleum ether. This effectively removes organically soluble impurities and yields a high-purity solid product, compound III.

[0032] In some embodiments of the present invention, in S3, the nitro reduction reaction includes one of catalytic hydrogenation, metal reduction, transfer hydrogenation, and sulfide reduction.

[0033] In some embodiments of the present invention, in S3, hydrogen and a catalyst are added during the catalytic hydrogenation reaction. The catalyst is one of palladium on carbon, platinum on carbon, and Raney nickel. The hydrogen dissociates on the surface of the metal catalyst, gradually reducing the nitro group.

[0034] During the metal reduction reaction, one or more of iron powder, stannous chloride, and zinc powder are added; the metal acts as an electron donor to reduce the nitro group in an acidic medium.

[0035] Palladium on carbon and a hydrogen donor are added during the transfer hydrogenation reaction. The hydrogen donor is one of ammonium formate, cyclohexene, and hydrazine hydrate. Organic molecules are used as hydrogen sources, and hydrogen atoms are transferred under the action of a catalyst.

[0036] In the reduction reaction of sodium sulfide, one or more of sodium sulfide, sodium hydrosulfide, ammonium sulfide, sodium dithionite, and sodium thiosulfate are added. Polysulfides, etc., are used as reducing agents for the selective reduction of nitro groups.

[0037] In some embodiments of the present invention, in S3, the nitro reduction reaction temperature is 0-40℃, the reaction time is 5-48h, the reaction is filtered, hydrochloric acid is added to the filtrate and the solution is concentrated under reduced pressure, the crude product is dissolved and crystallized, filtered and dried to obtain 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one.

[0038] In some embodiments of the present invention, in S4, the structural formula of compound V is as follows: The structure of compound V directly determines the substituents on rings A and B of the final camptothecin derivative.

[0039] In some embodiments of the present invention, in S4, the acidic conditions are achieved by adding p-toluenesulfonic acid monohydrate and one of toluene and N-methylpyrrolidone, and the ring-closure reaction is carried out at a temperature of 80-150°C for 5-24 hours. Toluene facilitates azeotropic dehydration and promotes the forward shift of the condensation equilibrium; N-methylpyrrolidone (NMP) is a high-boiling-point polar solvent that can dissolve a variety of intermediates.

[0040] In some embodiments of the present invention, in S4, after the cyclization reaction is completed and the temperature is lowered to room temperature, the resulting reaction solution is added to water and stirred, filtered to obtain a crude product, the crude product is added to methanol and stirred, filtered and dried to obtain a camptothecin derivative compound.

[0041] Example S1. 50 g of 2-nitroacetophenone, 15 g of paraformaldehyde, 45 mL of isopropylamine, and 2 mL of hydrochloric acid were added to 500 mL of isopropanol. The mixture was stirred and refluxed at 82 °C for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure. 200 mL of water and 10 mL of hydrochloric acid were added, and the aqueous layer was extracted with ethyl acetate to remove impurities. Sodium bicarbonate was added to adjust the pH of the aqueous layer to neutral. After extraction with ethyl acetate again, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 56.2 g of 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one, with a yield of 68%.

[0042] S2. 56.2 g of 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one and N,N-diisopropylethylamine obtained in S1 were added to 560 mL of dichloromethane, and 30.7 g of methanesulfonyl chloride was slowly added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, 560 mL of 1M dilute hydrochloric acid was added, and the mixture was separated. The organic phase was washed with 300 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was added to 170 mL of ethyl acetate and stirred to dissolve. 510 mL of petroleum ether was added dropwise to crystallize the product. After filtration and drying, 58.9 g of 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one was obtained, with a yield of 91%.

[0043] S3. 58.9 g of 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one obtained in S2 and 5.9 g of 7.5% palladium on carbon were added to 589 mL of methanol. Hydrogen gas was introduced, and the mixture was stirred at room temperature for 24 h to carry out the nitro reduction reaction. After filtration, 20 mL of hydrochloric acid was added to the filtrate and stirred. The mixture was concentrated under reduced pressure, and the crude product was added to 180 mL of ethyl acetate and stirred to dissolve. 540 mL of petroleum ether was added dropwise to crystallize the product. After filtration and drying, 49.5 g of 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one was obtained, with a yield of 93%.

[0044] S4, 9.3g of 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one obtained in S3 and 5g of compound V 3.3 g of p-toluenesulfonic acid monohydrate and 500 mL of toluene were mixed and subjected to a cyclization reaction at 110 °C for 8 h. After the cyclization reaction was completed, the mixture was cooled to room temperature, and the resulting reaction solution was added to 1.5 L of water and stirred for 0.5 h. After filtration, a crude product was obtained. The crude product was added to 50 mL of methanol and stirred. After filtration and drying, 8.4 g of camptothecin derivative (compound VI) was obtained, with a yield of 86%.

[0045] Test case The proton nuclear magnetic resonance (NMR) spectra of 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one (compound II), 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one (compound III), 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one (compound IV), and a camptothecin derivative (compound VI) were obtained as follows: Figures 1-4 As shown.

[0046] Depend on Figure 1 It can be seen that, 1 H NMR (400 MHz, Deuterium Oxide) 8.23 ​​(1 H, dd, J 8.3,1.1), 7.87 (1 H, td, J 7.6, 1.2), 7.76 (1 H, ddd, J 8.8, 7.6, 1.4), 7.58 (1H, dd, J 7.6, 1.4), 3.56 – 3.42 (3 H, m), 3.37 (1 H, t, J 6.2), 1.36 (6 H, d,J 6.6).

[0047] Depend on Figure 2 It can be seen that, 1 H NMR (400 MHz, Chloroform- d ) 8.14 (1 H, dd, J 8.3,1.2), 7.74 (1 H, td, J 7.5, 1.2), 7.62 (1 H, ddd, J 8.8, 7.6, 1.5), 7.43 (1H, dd, J 7.5, 1.4), 4.13 (1 H, hept, J 6.8), 3.64 – 3.56 (2 H, m), 3.26 –3.17 (2 H, m), 2.88 (3 H, s), 1.25 (6 H, d, J 6.8).

[0048] Depend on Figure 3 It can be seen that, 1 H NMR (400 MHz, DMSO- d 6) 7.75 (1 H, dd, J 8.3, 1.5), 7.25 (1 H, ddd, J 8.4, 6.9, 1.5), 7.20 (2 H, s), 6.76 (1 H, dd, J 8.3, 1.2), 6.55 (1 H, ddd, J 8.2, 6.9, 1.2), 3.94 (1 H, h, J 6.8), 3.45 – 3.36 (2 H, m), 3.26 – 3.18 (2 H, m), 2.94 (3 H, s), 1.16 (6 H, d, J 6.7).

[0049] Depend on Figure 4 It can be seen that, 1 H NMR (400 MHz, DMSO- d 6 ) 8.30 (1 H, d, J 8.7), 8.19 (1H, dd, J 8.4, 1.3), 7.87 (1 H, ddd, J 8.3, 6.8, 1.3), 7.77 (1 H, ddd, J 8.3,6.8, 1.3), 7.34 (1 H, s), 6.53 (1 H, s), 5.44 (2 H, s), 5.40 (2 H, s), 3.98 (1 H, p, J 6.7), 3.49 (2 H, dd, J 9.7, 6.0), 3.42 – 3.33 (2 H, m), 3.00 (3 H, s), 1.96 – 1.79 (2 H, m, J 7.2), 1.15 (6 H, d, J 6.7), 0.89 (3 H, t, J 7.3).

[0050] Therefore, the present invention employs the above-mentioned method for synthesizing camptothecin derivatives, which splits the complex camptothecin derivative into two easily prepared fragments: 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one and compound V. Finally, multiple rings and chemical bonds are constructed simultaneously through a one-step efficient ring-closing reaction, avoiding the yield decay caused by the stepwise accumulation of yields in traditional linear synthesis, and achieving an improvement in the overall yield.

[0051] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for synthesizing a camptothecin derivative, characterized in that: Includes the following steps: S1. Add 2-nitroacetophenone, paraformaldehyde, isopropylamine, and hydrochloric acid to isopropanol, heat and stir to react, concentrate under reduced pressure after the reaction is complete, extract to remove impurities in the aqueous layer, adjust the pH of the aqueous layer, extract again, dry the organic phase, filter and concentrate under reduced pressure to obtain 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one. S2. The 1-(2-nitrophenyl)-3-(isopropylamino)prop-1-one and N,N-diisopropylethylamine obtained in S1 are added to dichloromethane, and a methanesulfonylating agent is added to react at room temperature to obtain 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one. S3. Add the 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one obtained in S2 to methanol and stir to carry out nitro reduction reaction to obtain 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one. S4. The 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one obtained in S3 and compound V were subjected to a cyclization reaction under acidic conditions to obtain camptothecin derivatives.

2. The method for synthesizing a camptothecin derivative according to claim 1, characterized in that: In S1, the temperature for heating and stirring the reaction is 80-100℃, and the time is 1-24h.

3. The method for synthesizing a camptothecin derivative according to claim 1, characterized in that: In S2, the methanesulfonating agent includes one or more of methanesulfonyl chloride and methanesulfonic anhydride.

4. The method for synthesizing a camptothecin derivative according to claim 1, characterized in that: In S2, after the reaction is complete, dilute hydrochloric acid is added and the mixture is separated. The organic phase is washed, dried, filtered, and concentrated under reduced pressure. The crude product is dissolved, crystallized, filtered, and dried to obtain 1-(2-nitrophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one.

5. The method for synthesizing a camptothecin derivative according to claim 1, characterized in that: In S3, the nitro reduction reaction includes one of the following: catalytic hydrogenation, metal reduction, transfer hydrogenation, and sulfide reduction.

6. The method for synthesizing a camptothecin derivative according to claim 5, characterized in that: In S3, hydrogen and a catalyst are added during the catalytic hydrogenation reaction. The catalyst is one of palladium on carbon, platinum on carbon, and Raney nickel. One or more of iron powder, stannous chloride, and zinc powder are added during metal reduction reactions; Palladium on carbon and a hydrogen donor are added during the transfer hydrogenation reaction. The hydrogen donor is one of ammonium formate, cyclohexene, and hydrazine hydrate. One or more of sodium sulfide, sodium hydrosulfide, ammonium sulfide, sodium dithionite, and sodium thiosulfate are added during the sodium sulfide reduction reaction.

7. The method for synthesizing a camptothecin derivative according to claim 1, characterized in that: In S3, the nitro reduction reaction temperature is 0-40℃ and the reaction time is 5-48h. After the reaction, the product is filtered, hydrochloric acid is added to the filtrate and the solution is concentrated under reduced pressure. The crude product is dissolved and crystallized, filtered and dried to obtain 1-(2-aminophenyl)-3-(N-isopropyl-N-methanesulfonylamino)prop-1-one.

8. The method for synthesizing a camptothecin derivative according to claim 1, characterized in that: In S4, the structural formula of compound V is: .

9. The method for synthesizing a camptothecin derivative according to claim 1, characterized in that: In S4, the acidic conditions are achieved by adding either p-toluenesulfonic acid monohydrate or one of toluene and N-methylpyrrolidone, and the cyclization reaction is carried out at a temperature of 80-150℃ for 5-24 hours.

10. The method for synthesizing a camptothecin derivative according to claim 1, characterized in that: In S4, after the ring-closing reaction is complete and the mixture is cooled to room temperature, the resulting reaction solution is added to water and stirred. After filtration, a crude product is obtained. The crude product is then added to methanol and stirred. After filtration and drying, a camptothecin derivative is obtained.

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